1. Field of the Invention
This invention relates to a pharmaceutical dosage unit for oral administration containing 17β-estradiol-3-lower alkanoate, most preferably 17β-estradiol-3-acetate, that unexpectedly provides improved bioavailability of estrogen when orally administered to a human female in need of estrogen replacement therapy or receiving estrogen for contraceptive purposes. The invention also relates to a process for producing the pharmaceutical dosage unit.
2. Related Background Art
In the normal, healthy human female, 17β-estradiol is the principal estrogen produced by the functioning premenopausal ovary during each menstrual cycle [Lieveritz, R. W., Amer. J. of Obstetrics and Gynecology, Vol. 156, pp. 1289-1293, 1987]. Estrogen deficiency may occur due to disease, oophorectomy, traumatic injury or as a natural consequence of the aging process. As aging progresses, ovulation becomes less frequent and predictable, resulting in diminished production of 17β-estradiol. Gradual loss of ovarian function occurs naturally around 45-55 years of age leading to the eventual cessation of the menstrual cycle, that is, the menopause.
During normal ovulatory cycles ovarian production of 17β-estradiol ranges from 60-600 μg per day, resulting in circulating levels of 17β-estradiol in serum ranging from 40-400 μg/ml. Circulating 17β-estradiol levels vary during the monthly cycle in the premenopausal woman. At the menopause, when irreversible ovarian failure occurs, 17β-estradiol production decreases dramatically to less than 20 μg per day, giving circulating levels of the hormone in serum of less than 30 μg/ml. [Stumpf, P. G., Obstetrics and Gynaecology, Vol. 75 (suppl.) pp. 95-135, 1990]. This low level of estrogen production may result in typical postmenopausal symptoms [Marsh, M. S., et al., British Medical Bulletin, Vol. 48, pp. 426-457, 1992]. The physiological consequences of the fall in estradiol levels typically include vasomotor instability (hot flushes), urogenital atrophy and a loss of bone mineral mass leading to osteoporosis.
The most active, naturally occurring human estrogen is unbound 17β-estradiol. Hormone replacement therapy (HRT) seeks to counteract the detrimental effects associated with low circulating plasma estrogen levels by restoring these, as far as possible, to a premenopausal physiological status. It follows, therefore, that the preferential estrogen for HRT is 17β-estradiol and that the aim of HRT is to deliver this hormone at such a rate as to maintain physiological plasma levels of 17β-estradiol.
17β-Estradiol is not absorbed efficiently from the gastric mucosa following administration by the oral route and must, therefore, be formulated for administration in micronized form (to provide an increased surface area) or as a conjugate [Lobo, R. A., et al., J. of Reproductive Medicine, Vol. 37, pp. 77-84, 1992]. The term conjugate encompasses various esters of 17β-estradiol and estrogenic compounds, some of which are derived from equine sources. Examples of conjugates known in the art for the oral administration of estrogen for HRT include estradiol-3,17-diacetate, estradiol-17-acetate, estradiol-3,17-valerate, estradiol-3-valerate, estradiol-17-valerate, ethinyl estradiol, and equine estrogens. The latter are mixtures of estrogens purified from the urine of pregnant mares and containing sulphate and glucouronide derivatives, and equine-specific estrogens such as equilin not normally found in humans [Stumpf, 1990]. In addition, less potent metabolites of 17β-estradiol have been administered by this route, for example, estrone or its conjugates
A number of difficulties arise concerning the oral administration of estrogens. Although micronized 17β-estradiol is an efficient form of the natural hormone for its oral administration, micronization represents an additional process for pharmaceutical production, with associated increased costs and inconvenience. Micronized 17β-estradiol has been shown to be equivalent in pharmacokinetic terms to the oral administration of 17β-estradiol valerate, which is metabolised to the parent hormone in vivo. 17β-estradiol valerate is a highly lipophilic ester with no measurable aqueous solubility, as are other ester derivatives of 17β-estradiol administered by the oral route [Woolfson, D., et al., J. of Controlled Release, Vol. 61, pp. 319-328, 1999]. Orally administered 17β-estradiol and its various ester and equine conjugates undergo extensive first-pass hepatic metabolism, resulting in poor bioavailability by the oral route. In addition, hepatic metabolism causes undesirable non-physiological circulating levels of the metabolite estrone and elevation of hepatic proteins. Conjugated equine estrogens, in particular, exert a profound hepatic effect [Kuhl, H., Maturitas, Vol. 12, pp. 171-197, 1990] and are thus clinically less desirable than derivatives of the parent hormone. Oral administration of 17β-estradiol or its conjugates requires a significantly higher dose for clinical efficacy compared to non-oral routes [Powers, M., et al., Amer. J. of Obstetrics and Gynecology, Vol. 152, pp. 1099-1106, 1985].
Much of the prior art literature for preparation of oral pharmaceutical formulations of steroids such as estradiol comprises broad disclosures of solution or suspension wet granulation methods (for example, Pasquale, U.S. Pat. No. 4,544,554; Lemer, U.S. Pat. No. 3,568,828; Greaves, U.S. Pat. No. 5,976,570) or dry mixing using specialized excipients (for example, DeHaan, U.S. Pat. No. 5,382,434; Greaves, U.S. Pat. No. 5,928,668).
Dry mixing of low dose drugs is especially prone to significant lack of uniformity in drug distribution, even with the use of specialized excipients. Wet granulation using organic solvents such as chloroform, as described by Lemer, is generally unacceptable from an environmental, cost, and health and safety standpoint. On the other hand, aqueous wet granulation (e.g. Greaves, U.S. Pat. No. 5,976,570) could readily induce hydrolysis of ester derivatives of 17β-Estradiol. A method for producing uniform, stable orally administered estrogen products with improved bioavailability is therefore highly desirable.
This invention discloses a method for improving the bioavailability of orally administered estrogen in the form of 17β-estradiol-3-lower alkanoate. Parenteral administration of estradiol esters such as estradiol valerate, estradiol cypiorate and estradiol benzoate are well known. 17β-Estradiol-3-acetate has been shown to be an efficient form of estrogen for intravaginal delivery of HRT ([Woolfson et al, 1999], and McClay U.S. Pat. No. 5,855,906), but there has been no disclosure of its surprising advantages when formulated for oral delivery. 17β-Estradiol-3-acetate is known to have an aqueous solubility twice that of 17β-estradiol and vastly greater than that of conventional 17β-estradiol esters such as the valerate, benzoate and 17-acetate esters [Woolfson et al, 1999]. It is well known in the art that esterification of a drug to provide a more lipophilic derivative is a means of improving drug absorption across epithelial membranes, and thus bioavailability. Thus, the highly lipophilic esters of 17β-estradiol are all well known to be absorbed via the oral route, suggesting that the more water-soluble 17β-estradiol-3-acetate would be an unlikely candidate for improving bioavailability of the hormone via the oral route.